title: Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice.
abstract: During prion disease, an increase in misfolded prion protein (PrP) generated by prion replication leads to sustained overactivation of the branch of the unfolded protein response (UPR) that controls the initiation of protein synthesis. This results in persistent repression of translation, resulting in the loss of critical proteins that leads to synaptic failure and neuronal death. We have previously reported that localized genetic manipulation of this pathway rescues shutdown of translation and prevents neurodegeneration in a mouse model of prion disease, suggesting that pharmacological inhibition of this pathway might be of therapeutic benefit. We show that oral treatment with a specific inhibitor of the kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase), a key mediator of this UPR pathway, prevented UPR-mediated translational repression and abrogated development of clinical prion disease in mice, with neuroprotection observed throughout the mouse brain. This was the case for animals treated both at the preclinical stage and also later in disease when behavioral signs had emerged. Critically, the compound acts downstream and independently of the primary pathogenic process of prion replication and is effective despite continuing accumulation of misfolded PrP. These data suggest that PERK, and other members of this pathway, may be new therapeutic targets for developing drugs against prion disease or other neurodegenerative diseases where the UPR has been implicated.
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Moreno
authors.forename: Mark
authors.initials: M
authors.lastname: Halliday
authors.forename: Colin
authors.initials: C
authors.lastname: Molloy
authors.forename: Helois
authors.initials: H
authors.lastname: Radford
authors.forename: Nicholas
authors.initials: N
authors.lastname: Verity
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Axten
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Ortori
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: David A
authors.initials: DA
authors.lastname: Barrett
authors.forename: Giovanna R
authors.initials: GR
authors.lastname: Mallucci
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D017096:Prion Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011328:Prions; D014176:Protein Biosynthesis / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000225:Adenine; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D018696:Neuroprotective Agents; D011328:Prions; D019892:eIF-2 Kinase; C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine